title: Absence of the GPR37/PAEL receptor impairs striatal Akt and ERK2 phosphorylation, DeltaFosB expression, and conditioned place preference to amphetamine and cocaine.
abstract: The orphan G-protein-coupled receptor 37 (GPR37) colocalizes with the dopamine (DA) transporter (DAT) in mouse nigrostriatal presynaptic membranes, and its genetic ablation in homozygous null-mutant (GPR37-KO) mice provokes the marked increase of plasma membrane expression of DAT, alteration of psychostimulant-induced locomotor activity, and reduction of catalepsy induced by DA-receptor antagonists. We report that extracts from GPR37-KO mice displayed biochemical alterations of the nigrostriatal signaling pathways mediated by D1 and D2 dopaminergic receptors. Null-mutant mice showed an increase of the basal phosphorylation level of the D2-regulated Akt kinase. The basal phosphorylation of the D1-activated ERK2 kinase was not altered, but acute treatments with amphetamine or cocaine failed to produce its specific increase, as detected in samples from wild-type littermates. Furthermore, the chronic administration of cocaine to GPR37-KO mice did not increase the expression of the ΔFosB transcription factor isoforms. Consistently, behavioral analysis showed that null-mutant animals did not respond to the incentive properties of amphetamine or cocaine, in conditioned place preference tests. Thus, the lack of GPR37 affects both ERK2- and Akt-mediated striatal signaling pathways, impairing the biochemical and behavioral responses typically induced by acute and chronic administration of psychostimulant drugs.
authors.affiliation: Istituto di Biologia Cellulare-Consiglio Nazionale delle Ricerche, Campus A. Buzzati-Traverso, Via E. Ramarini 32, I-00015 Monterotondo Scalo, Rome, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Marazziti
authors.forename: Chiara
authors.initials: C
authors.lastname: Di Pietro
authors.forename: Silvia
authors.initials: S
authors.lastname: Mandillo
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Golini
authors.forename: Rafaele
authors.initials: R
authors.lastname: Matteoni
authors.forename: Glauco P
authors.initials: GP
authors.lastname: Tocchini-Valentini
mesh_terms: D000661:Amphetamine / Q000378:metabolism; D000818:Animals; D000697:Central Nervous System Stimulants / Q000378:metabolism; D003042:Cocaine / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*
chemical_list: D000697:Central Nervous System Stimulants; D018765:Dopamine Uptake Inhibitors; C483819:Fosb protein, mouse; C509804:Gpr37 protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D043562:Receptors, G-Protein-Coupled; D000661:Amphetamine; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D003042:Cocaine